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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Functional relevance of the histone γH2Ax in the response to DNA damaging agents
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Functional relevance of the histone γH2Ax in the response to DNA damaging agents

机译：组蛋白γH2Ax在对DNA损伤剂反应中的功能相关性

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摘要

The phosphorylation of H2Ax on its S139 site,γH2Ax, is important during DNA double-strand repair and is considered necessary for assembly of repair complexes, but its functional role after other kinds of DNA damage is less clear. We have measured the survival of isogenic mouse cell lines with the H2Ax gene knocked out, and replaced with wild-type or mutant (S139A) H2Ax genes, exposed to a range of agents with varied mechanisms of DNA damage. Knockout and mutant cells were sensitive to γ-rays, etoposide, temozolamide, and endogenously generated reactive oxygen species, each of which can include double-strand breaks among their spectra of DNA lesions. The absence or mutation of H2Ax had no influence on sensitivity to cisplatin or mitomycin C. Although UV light induced the highest levels of γH2Ax, mutation of S139 had no influence on UV sensitivity or the UV DNA damage response. Complete loss of H2Ax reduced the survival of cells exposed to UV light and reduced pChk1 induction, suggesting that sites other than S139 may impact the ATR-pChk1 pathway. The relative intensity of γH2Ax measured in Western blots in wild-type cells did not correlate with the functional importance of yH2Ax. The use of yH2Ax as a general biomarker of DNA damage is therefore potentially misleading because it is not an unambiguous indicator of double-strand breaks, and a significant fraction of DNA repair, especially involving nucleotide excision or crosslink repair, can occur without functional involvement of γH2Ax.
机译：H2Ax在其S139位点（γH2Ax）的磷酸化在DNA双链修复过程中很重要，并且被认为是组装修复复合物所必需的，但在其他类型的DNA损伤后其功能作用尚不清楚。我们已经测量了敲除H2Ax基因并被野生型或突变（S139A）H2Ax基因取代的同基因小鼠细胞系的存活，这些基因暴露于具有各种DNA损伤机制的各种试剂中。敲除和突变细胞对γ射线，依托泊苷，替莫唑胺和内源性产生的活性氧都敏感，它们各自的DNA损伤谱中都可能包含双链断裂。 H2Ax的缺失或突变对顺铂或丝裂霉素C的敏感性没有影响。尽管紫外线诱导了最高水平的γH2Ax，但S139的突变对紫外线敏感性或UV DNA损伤反应没有影响。 H2Ax的完全丧失降低了暴露于紫外线下的细胞的存活并降低了pChk1的诱导，这表明除S139以外的其他位点可能会影响ATR-pChk1途径。在Western印迹中在野生型细胞中测得的γH2Ax的相对强度与yH2Ax的功能重要性无关。因此，将yH2Ax用作DNA损伤的一般生物标志物可能会产生误导，因为它不是双链断裂的明确指标，并且在不进行功能性干预的情况下，可以发生很大一部分DNA修复，特别是涉及核苷酸切除或交联修复。 γH2Ax。

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    Ingrid Revet; Luzviminda Feeney; Stephanie Bruguera; Wade Wilson; Tiffany K. Dong; Dennis H. Oh; David Dankort; James E. Cleaver;

  • 作者单位

    Department of Dermatology, University of California, San Francisco, CA 94143-0808;

    Department of Dermatology, University of California, San Francisco, CA 94143-0808;

    Department of Dermatology, University of California, San Francisco, CA 94143-0808;

    Department of Dermatology, University of California, San Francisco, CA 94143-0808;

    Department of Dermatology, University of California, San Francisco, CA 94143-0808 Dermatology Research Unit, Veteran's Affairs Medical Center, San Francisco, CA 94121;

    Department of Dermatology, University of California, San Francisco, CA 94143-0808 Dermatology Research Unit, Veteran's Affairs Medical Center, San Francisco, CA 94121;

    Department of Biology, McGill University, Montreal, QC, Canada H3G 0B1;

    Department of Dermatology, University of California, San Francisco, CA 94143-0808;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    alkylation; rotenone; caffeine; poly(adp-ribose) polymerase; veliparib;

    机译：烷基化鱼藤酮;咖啡因;聚（adp-核糖）聚合酶;veliparib;

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